Method for forming a molded two-layer ocular implant

ABSTRACT

The present invention generally relates to local therapies for the eye and, more particularly, to shaped controlled-release ocular implant devices, including methods for making and using such devices, for delivery of therapeutic agents to the eye. A molded two-layer ocular implant comprises a therapeutic agent for treatment or prevention of a disorder of the eye. The implant comprises a polymer layer and a silicone adhesive layer with a therapeutic agent interspersed therein and joined to the polymer layer. This implant is for placement in the sub-Tenon&#39;s space of the eye and provides sustained release of the therapeutic agent during the treatment or prevention of the disorder of the eye.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. § 371 U.S. National Stage Entry ofInternational Application No. PCT/US2014/036370 filed May 1, 2014, whichclaims priority to U.S. Provisional Patent Application No. 61/818,568,filed May 1, 2013 entitled Two-layer ocular implant, the contents ofeach of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to local therapies for the eyeand, more particularly, to curved controlled-release ocular implantdevices, including methods for making and using such devices, fordelivery of therapeutic agents to the eye.

BACKGROUND OF THE INVENTION

In the treatment of many diseases and disorders of the eye, andespecially in the case of degenerative or persistent conditions,implantable sustained-release delivery devices have been desired thatwould continuously administer a therapeutic agent to the eye for aprolonged period of time.

Local ocular implants of a wide variety of constructions and placementshave been proposed heretofore for dispensing a therapeutic drug to theeye.

The present invention provides a shaped ocular implant with improvedcomfort and functionality.

SUMMARY OF THE INVENTION

The present invention provides a shaped ocular implant for delivery ofdrugs to the eye for treatment of diseases and disorders of the eye.

Various ocular implants have been described. For instance, U.S. Pat. No.4,014,335 describes an ocular drug delivery device placed in thecul-de-sac between the sclera and lower eyelid for administering thedrug and acting as a reservoir. The ocular device is characterizedtherein as administering drug to the eye in a controlled, continuousdosage rate over a prolonged time. To accomplish this, the ocular devicecomprises a three-layered laminate of polymeric materials holding thedrug in a central reservoir region of the laminate. The drug diffusesfrom the reservoir through at least one of the polymeric layers of thelaminate.

U.S. Pat. No. 5,773,021 describes bioadhesive ophthalmic inserts thatare placed in the conjunctival sac, in which the inserts are prepared byextrusion, thermoforming, or heat compression of a polymeric materialmatrix and the drug to be delivered. The polymeric matrix comprises awater-soluble biocompatible polymer, such as hydroxyalkyl celluloses,maltodextrins, chitosans, modified starches or polyvinyl alcohols; awater-insoluble biocompatible polymer such as an alkyl cellulose; andwhere applicable a bioadhesive polymer such as polyvinyl carboxylic acidtype polymers or certain bioadhesive polysaccharides or derivativesthereof. The ophthalmic inserts are characterized therein as intendedfor the prolonged and controlled release of a medicinal substance.

U.S. Pat. No. 5,773,019 describes a continuous release drug deliveryimplant which, among other mentioned places, can be mounted either onthe outer surface of the eye or within the eye. A drug core is coveredby a polymer coating layer that is permeable to the low solubility agentwithout being release rate limiting. Descriptions include a coating ofcyclosporine A (CsA) drug cores with one or multiple coatings ofpolyvinyl alcohol solution, followed by heating to 104, 110 or 120° C.,presumably to cross link and harden the coating(s) in place around thecore. Also described is an implant prepared by fixing a pellet directlyover a smaller hole formed in a silicone film, followed by a suturebeing placed around the pellet in a gapped relationship thereto, andthen the entire assembly is coated again with silicone to form theimplant. The ocular device is characterized therein as giving acontinuous release to an affected area, once implanted, and producinglong-term sustained tissue and vitreous levels at relatively lowconcentrations.

U.S. Pat. No. 5,378,475 describes a sustained-release implant forinsertion into the vitreous cavity of the eye. The implant has a firstimpermeable coating, such as ethylene vinyl acetate, surrounding most,but not all, of a drug reservoir and a second permeable coating, such asa permeable crosslinked polyvinyl alcohol, disposed over the firstcoating including the region where the first coating does not cover thedrug reservoir, to provide a location through which the drug can diffuseout of the implant. The implant also has a tab, which can be used tosuture the device in place in the eye. The implant devices are preparedby applying coating solutions, such as by dipping, spraying or brushing,of the various coating layers around the drug reservoir.

U.S. Pat. No. 5,725,493 describes an ocular implant device for providingdrugs to the vitreous cavity over a period of time. The drug reservoiris attached to the outside of the eye with a passageway permittingmedicament to enter the vitreous cavity of the eye.

U.S. Pat. Nos. 6,713,081 and 7,658,364 describe dual mode and singularmode ocular therapeutic agent delivery devices. These devices aresuitable for subconjunctival and intravitreal placement.

The above-listing of publications describing prior ocular implantsystems is intended to be only illustrative in nature, and notexhaustive.

Local ocular implants avoid the shortcomings and complications that canarise from systemic therapies of eye disorders. For instance, oraltherapies for the eye fail to provide sustained-release of the drug intothe eye. Instead, oral therapies often only result in negligible actualabsorption of the drug in the ocular tissues due to low bioavailabilityof the drug. Ocular drug levels following systemic administration ofdrugs is usually limited by various blood/ocular barriers (i.e., tightjunctions between the endothelial cells of the capillaries). Thesebarriers limit the amounts of drugs entering the eye via systemiccirculation. In addition, variable gastrointestinal drug absorptionand/or liver metabolism of the medications can lead to dosage-dependentand inter-individual variations in vitreous drug levels. Moreover,adverse side effects have been associated with systemic administrationof certain drugs to the eyes.

For instance, systemic treatments of the eye using the immune responsemodifier cyclosporine A (CsA) have the potential to cause nephrotoxicityor increase the risk of opportunistic infections, among other concerns.This is unfortunate since CsA is a recognized effective active agent fortreatment of a wide variety of eye diseases and indications, such asendogenous or anterior uveitis, corneal transplantation, Behçet'sdisease, vernal or ligneous keratoconjunctivitis, dry eye syndrome, andthe like. In addition, rejection of corneal allografts and stem cellgrafts occurs in up to 90% of patients when associated with risk factorssuch as corneal neovascularization. CsA has been identified as apossibly useful drug for reducing the failure rate of such surgicalprocedures for those patients. Thus, other feasible delivery routes forsuch drugs that can avoid such drawbacks associated with systemicdelivery are in demand.

Apart from implant therapies, other local administration routes for theeye have included topical delivery. Such therapies include ophthalmicdrops and topical ointments containing the medicament. Tight junctionsbetween corneal epithelial cells limit the intraocular penetration ofeye drops and ointments. Topical delivery to the eye surface viasolutions or ointments can in certain cases achieve limited, variablepenetration of the anterior chamber of the eye. However, therapeuticlevels of the drug are not achieved and sustained in the middle or backportions of the eye. This is a major drawback, as the back (posterior)chamber of the eye is a frequent site of inflammation or otherwise thesite of action where, ideally, ocular drug therapy should be targetedfor many indications.

Therapeutic agents for the treatment of the eye can be broadly dividedinto two groups: hydrophilic compounds and lipophilic compounds.Hydrophilic compounds are well established and have a wide range oftherapeutic uses due to the ease with which they dissolve in water.However, hydrophilic compounds do not cross lipid barriers easily and,in the eye specifically, lymphatic clearance of compounds in theepisclera contributes to the difficulty of maintaining therapeuticlevels of the drug as mentioned herein.

Lipophilic compounds do not dissolve easily in an aqueous solution, butdue to their chemical nature may easily cross lipid membranes includingthe blood-neural barrier in the brain or the blood-retinal barrier inthe eye. Therefore, lipophilic compounds represent an emerging class oftherapeutic drugs that may circumvent difficulties seen in existing drugtreatment methodologies. In some embodiments, the lipophilic agents ordrugs employed in the implants of the invention collect, concentrate,aggregate or otherwise have an increased concentration in retinaltissues. This retinal trapping or sink effect provides for increasedefficacy. Such efficacy may be measured by an increase in one or morephenotypic effects, half-life of the drug at a particular retinal orretinal-related location or durational clinically beneficial effect.

In some embodiments retinal trapping results in an increase of drugsubstance of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% or moreof drug to the retinal tissue or cells. In some embodiments, the ratioof drug in the retinal tissue, e.g., retinal trap, compared to eithersurrounding tissue or drug remaining in the implant at any time is 1.5to 1, 2 to 1, 3 to 1, 4 to 1 or greater than 5 to 1.

Age-related macular degeneration (AMD) is a common disease associatedwith aging that gradually impairs sharp, central vision. There are twocommon forms of AMD: dry AMD and wet AMD. About ninety percent of thecases of AMD are the dry form, caused by degeneration and thinning ofthe tissues of the macula; a region in the center of the retina thatallows people to see straight ahead and to discern fine details.Although only about ten percent of people with AMD have the wet form, itposes a much greater threat to vision. With the wet form of the disease,rapidly growing abnormal blood vessels known as choroidal neovascularmembranes (CNVM) develop beneath the macula. These vessels leak fluidand blood that destroy light sensing cells, thereby producing blindingscar tissue, with resultant severe loss of central vision. Wet AMD isthe leading cause of legal blindness in the United States for peopleaged sixty-five or more with approximately 25,000 new cases diagnosedeach year in the United States. Ideally, treatments of the indicationwould include inducing an inhibitory effect on the choroidalneovascularization (CNV) associated with AMD. The macula is located atthe back of the eye and therefore treatment of CNVM by topical deliveryof pharmacological agents to the tissues of the macula tissues is notpossible. Intravitreal injections of anti-angiogenic agents, laserphotocoagulation, photodynamic therapy, and surgical removal arecurrently used to treat CNVM. Unfortunately, the recurrence rate usingsuch methods exceeds 50-90% in some cases. In most cases indefinitetreatment is required.

As an approach for circumventing the barriers encountered by localtopical delivery, one local therapy route for the eye has involveddirect intravitreal injection of a treatment drug through the sclera(i.e., the spherical, collagen-rich outer covering of the eye). However,the intravitreal injection delivery route tends to result in a shorthalf-life and rapid clearance without sustained release capability beingattained. Consequently, weekly to monthly injections are frequentlyrequired to maintain therapeutic ocular drug levels. This is notpractical for many patients.

Given these drawbacks, the use of implant devices placed in or adjacentto the eye tissues to deliver therapeutic drugs thereto should offer agreat many advantages and opportunities over the rival therapy routes.Despite the variety of ocular implant devices which have been describedand used in the past, the full potential of the therapy route has notbeen realized. Among other things, prior ocular implant devices deliverthe drug to the eye tissues via a single mode of administration for agiven treatment, such as via slow constant rate infusion at low dosage.However, in many different clinical situations, such as with CNVM inAMD, this mode of drug administration might be a sub-optimal oculartherapy regimen.

Another problem exists with previous ocular implants, from aconstruction standpoint, insofar as preparation techniques thereof haverelied on covering the drug pellet or core with a permeable polymer bymulti-wet coating and drying approaches. Such wet coating approaches canraise product quality control issues such as an increased risk ofdelamination of the thinly applied coatings during subsequent dippings,as well as thickness variability of the polymer around the drug pelletsobtained during hardening. Additionally, increased production costs andtime from higher rejection rates and labor and an increased potentialfor device contamination from additional handling are known problemswith present implant technology.

Accordingly, certain aspects of the present invention provide localtreatment of a variety of eye diseases. Other aspects of the presentinvention also provide a method for the delivery of pharmaceuticals tothe eye to effectively treat eye disease, while reducing or eliminatingthe systemic side effects of these drugs. Certain aspects of the presentinvention also provide shaped sustained-release ocular implants foradministration of therapeutic agents to the eye for prolonged periods oftime. Additionally, certain aspects of the present invention provideapproaches to alter the areas of the eye that are affected by diffusionof drugs from sustained-release ocular implants. Certain aspects of thepresent invention also provide methods for making shaped ocular implantswith reduced product variability.

Other aspects of the present invention also provide methods for makingshaped ocular implants well-suited for ocular treatment trials usinganimal models. Other advantages and benefits of aspects of the presentinvention will be apparent from consideration of the presentspecification.

In these and other ways described below, the inventive implants offer amyriad of advantages, improvements, benefits, and therapeuticopportunities. The inventive implants are highly versatile and can betailored to enhance the delivery regimen both in terms of administrationmode(s) and type(s) of drugs delivered. The implants of this inventionpermit continuous release of therapeutic agents into the eye over aspecified period of time, which can be weeks, months, or even years asdesired. As another advantage, the inventive implant systems of thisinvention require intervention only for initiation and termination ofthe therapy (i.e., removal of the implant). Patient compliance issuesduring a regimen are eliminated. The time-dependent delivery of one ormore drugs to the eye by this invention makes it possible to maximizethe pharmacological and physiological effects of the eye treatment. Theinventive implants have human and veterinary applicability.

In one aspect of the present invention, there is provided a method forforming a molded two-layer ocular implant, the implant comprising atherapeutic agent for treatment or prevention of a disorder of the eye,the method comprising: a) dispensing a polymer into a curved depressionon a mold body to form a polymer layer having a curved external surfacein contact with the bottom of the curved depression and furthercomprising an exposed upper surface; b) generating a curvature in theexposed upper surface of the polymer layer, thereby forming a curvedpolymer layer interface surface; c) curing the polymer layer, therebyproviding a hardened curved polymer layer interface surface; d)dispensing a silicone adhesive comprising the therapeutic agentdispersed therein onto the hardened interface surface to provide asilicone layer with an exposed surface; e) generating a curvature in theexposed surface of the silicone layer thereby forming a curvedeye-contacting surface; and f) curing the silicone layer such that thefirst layer and second layer are fixed to each other, thereby formingthe molded two-layer ocular implant.

Another aspect of the present invention is a method for forming a moldedtwo-layer ocular implant, the implant comprising a therapeutic agent fortreatment or prevention of a disorder of the eye, the method comprising:a) dispensing a polymer into a curved depression on a first mold body toform a polymer layer having a curved external surface in contact withthe bottom of the curved depression and further comprising an exposedupper polymer surface; b) generating a curvature in the exposed uppersurface of the polymer layer, thereby forming a curved polymer layerinterface surface; c) curing the polymer layer to produce a curedpolymer layer, d) dispensing a silicone adhesive comprising thetherapeutic agent dispersed therein into second curved depression on asecond mold body to provide a silicone layer with a curved siliconelayer interface surface in contact with the bottom of the curveddepression and further comprising an exposed upper silicone surface; e)generating a curvature in the exposed silicone surface, thereby forminga curved eye-contacting surface; f) curing the silicone layer to producea cured silicone layer; and g) joining the cured polymer layer to thecured silicone layer by attachment of the polymer layer interfacesurface to the silicone layer interface surface with biocompatibleadhesive. In certain embodiments, the adhesive is pressure sensitive. Incertain embodiments, the pressure sensitive adhesive may comprise any ofthose from DOW CORNING® such as BIO-PSA 7-4302 or other such adhesivesfrom the DOW CORNING® catalog, the contents of which are incorporatedherein by reference in their entirety.

In certain embodiments, the implant is circular or oval-shaped.

In certain embodiments, steps b) and e) are performed using animpression body with a curved protrusion for generating the curvature inthe exposed surface of the polymer layer and the exposed surface of thesilicone layer.

In certain embodiments, step b) is performed using a first impressionbody comprising a first curved protrusion for generating the curvaturein the exposed surface of the polymer layer and step e) is performedusing a second impression body comprising a second curved protrusion forgenerating the curvature in the exposed surface of the silicone layer,wherein the curvature dimensions of the first and second curvedprotrusions are different.

In certain embodiments, the polymer layer is resistant to diffusion ofthe therapeutic agent from the silicone layer.

In certain embodiments, the polymer layer is substantially impermeableto diffusion of the therapeutic agent from the silicone layer.

In certain embodiments, the polymer is polyvinyl acetate, cross-linkedpolyvinyl alcohol, cross-linked polyvinyl butyrate, ethyleneethylacrylate co-polymer, polyethyl hexylacrylate, polyvinyl chloride,polyvinyl acetals, plasiticized ethylene vinylacetate copolymer,polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer,polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides,polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinylchloride, plasticized nylon, plasticized soft nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene,polyvinylidene chloride, polyacrylonitrile, cross-linkedpolyvinylpyrrolidone, polytrifluorochloroethylene, chlorinatedpolyethylene, poly(1,4′-isopropylidene diphenylene carbonate),vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethylfumarate copolymer, silicone rubbers, medical gradepolydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonatecopolymers, vinylidene chloride-vinyl chloride copolymer, vinylchloride-acrylonitrile copolymer or vinylidene chloride-acrylonitridecopolymer.

In certain embodiments, the polymer layer and the silicone layer areeach about 1 mm thick.

In certain embodiments, the polymer layer and/or the silicone layerfurther comprise an agent that blocks lymphatic absorption of thetherapeutic agent.

In certain embodiments, the silicone layer further comprises anophthalmic permeation agent that increases ocular permeability of thetherapeutic agent into the eye.

In certain embodiments, the ophthalmic permeation agent ismethylsulfonylmethane.

In certain embodiments, the radius of curvature of the curvedeye-contacting surface of the silicone layer ranges from between about 5mm to about 6 mm.

In certain embodiments, the resulting molded implant is circular with adiameter ranging between about 1 mm and 8 mm.

In certain embodiments, the resulting molded implant is circular with adiameter ranging between about 1 mm and 3 mm.

In certain embodiments, the therapeutic agent is a nuclear factor(erythroid-derived 2)-like 2 enhancer (Nrf2 regulator).

In certain embodiments, the Nrf2 regulator is sulforaphane.

In certain embodiments, the therapeutic agent is selected from the groupconsisting of fumagillin analogs, minocycline, fluoroquinolone,cephalosporin antibiotics, herbimycon A, tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,oxytetracycline, chloramphenicol, gentamicin, erythromycin,antibacterial agents, sulfonamides, sulfacetamide, sulfamethizole,sulfoxazole, nitrofurazone, sodium propionate, antiviral agents,idoxuridine, famvir, trisodium phosphonoformate, trifluorothymidine,acyclovir, ganciclovir, DDI, AZT, protease and integrase inhibitors,anti-glaucoma agents, beta blockers, timolol, betaxolol, atenolol,prostaglandin analogues, hypotensive lipids, carbonic anhydraseinhibitors, antiallergenic agents, antazoline, methapyriline,chlorpheniramine, pyrilamine, prophenpyridamine, anti-inflammatoryagents, hydrocortisone, leflunomide, dexamethasone phosphate,fluocinolone acetonide, medrysone, methylprednisolone, prednisolonephosphate, prednisolone acetate, fluoromethalone, betamethasone,triamcinolone acetonide, adrenalcortical steroids and their syntheticanalogues, 6-mannose phosphate, antifungal agents, fluconazole,amphotericin B, liposomal amphotericin B, voriconazole, imidazole-basedantifungals, tiazole antifungals, echinocandin-like lipopeptideantibiotics, lipid formulations of antifungals, polycations, polyanions,suramine, protamine, decongestants, phenylephrine, naphazoline,tetrahydrazoline, anti-angiogenesis compounds including those that canbe potential anti-choroidal neovascularization agents,2-methoxyestradiol and its analogues, 2-propynl-estradiol,2-propenyl-estradiol, 2-ethoxy-6-oxime-estradiol, 2-hydroxyestrone,4-methoxyestradiol, VEGF antagonists, VEGF antibodies and VEGF antisensecompounds, angiostatic steroids, anecortave acetate and its analogues,17-ethynylestradiol, norethynodrel, medroxyprogesterone, mestranol,androgens with angiostatic activity, ethisterone, thymidine kinaseinhibitors, adrenocortical steroids and their synthetic analogues,fluocinolone acetonide, triamcinolone acetonide, immunological responsemodifying agents, cyclosporineA, Prograf (tacrolimus), macrolideimmunosuppressants, mycophenolate mofetil, rapamycin, muramyl dipeptide,vaccines, anti-cancer agents, 5-fluorouracil, platinum coordinationcomplexes, cisplatin, carboplatin, adriamycin, antimetabolites,methotrexate, anthracycline antibiotics, antimitotic drugs, paclitaxel,docetaxel, epipdophylltoxins, etoposide, nitrosoureas, carmustine,alkylating agents, cyclophosphamide, arsenic trioxide, anastrozole,tamoxifen citrate, triptorelin pamoate, gemtuzumab ozogamicin,irinotecan hydrochloride, leuprolide acetate, bexarotene, exemestrane,epirubicin hydrochloride, ondansetron, temozolomide,topoteanhydrochloride, tamoxifen citrate, irinotecan hydrochloride,trastuzumab, valrubicin, gemcitabine HCl, goserelin acetate,capecitabine, aldesleukin, rituximab, oprelvekin, interferon alfa-2a,letrozole, toremifene citrate, mitoxantrone hydrochloride, irinotecanHeL, topotecan HCl, etoposide phosphate, amifostine, antisense agents,antimycotic agents, miotic and anticholinesterase agents, pilocarpine,eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholineiodine, demecarium bromide, mydriatic agents such as atropine sulfate,cyclopentane, homatropine, scopolamine, tropicamide, eucatropine,hydroxyamphetamine, differentiation modulator agents, sympathomimeticagents epinephrine, anesthetic agents, lidocaine, benzodiazepam,vasoconstrictive agents, vasodilatory agents, polypeptides, proteinagents, angiostatin, endostatin, matrix metalloproteinase inhibitors,platelet factor 4, interferon-gamma, insulin, growth hormones, insulinrelated growth factor, heat shock proteins, humanized antiIL2 receptormAb (Daclizumab), etanercept, mono and polyclonal antibodies, cytokines,antibodies to cytokines, neuroprotective agents such as calcium channelantagonists including nimodipine and diltiazem, neuroimmunophilinligands, neurotropins, memantine, NMDA antagonists, acetylcholinesteraseinhibitors, estradiol and analogues, vitamin B12 analogues,alpha-tocopherol, NOS inhibitors, antioxidants, glutathione, superoxidedismutase, cobalt, copper, neurotrophic receptors, Akt kinase, growthfactors, nicotinamide (vitamin B3), alpha-tocopherol (vitamin E),succinic acid, dihydroxylipoic acid, fusidic acid, celltransport/mobility impending agents, colchicine, vincristine,cytochalasin B, carbonic anhydrase inhibitor agents, integrinantagonists and lubricating agents.

In certain embodiments, the therapeutic agent is a lipophilic agent. Incertain embodiments, the lipophilic therapeutic agent is selected fromthe group consisting of Idebenone, rapamycin, 2-cyano-3,12dioxooleana-1,9 dien-28-imidazolide (CDDO-Im),2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide(CDDO-ethyl amide), and 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oicacid trifluoroethyl amide (CDDO-TFEA).

In certain embodiments, the polymer layer and/or the silicone layerfurther comprise a nutraceutical oil.

In certain embodiments, the nutraceutical oil is omega-3 fish oil.

In certain embodiments, the silicone layer further comprises anexcipient that improves the release of drug.

In certain embodiments, the excipient is selected from one or more ofisopropyl myristate, levomenthol, propylene and tetraglycol.

Another aspect of the invention is a two-layer implant formed by themethods described herein. The implant of certain embodiments may be usedfor implantation into the sub-Tenon's space of a human. The implant ofother embodiments may be used for implantation into the sub-Tenon'sspace of a rodent.

Another aspect of the invention is a molded two-layer ocular implantcomprising a therapeutic agent for treatment or prevention of a disorderof the eye, the implant comprising: a first hardened layer comprising apolymer, the first hardened layer comprising curvature at both surfaces;and a second hardened layer comprising a silicone adhesive and thetherapeutic agent, the second hardened layer and comprising curvature atboth surfaces.

In certain embodiments, the curvature of one surface of the firsthardened layer and the curvature of one surface of the second layer areboth formed using an impression body with a curved protrusion.

In certain embodiments, the first and second hardened layers are definedas follows: the curvature of a first surface of the first hardened layeris formed by dispensing the polymer into a mold body; the curvature of asecond surface of the first hardened layer is formed by a first curvedprotrusion on a first impression body; the curvature of a first surfaceof the second hardened layer is formed by dispensing the siliconeadhesive onto the curvature of the second surface of the first hardenedlayer; and the curvature of a second surface of the second hardenedlayer is formed by a second curved protrusion on a second impressionbody.

In certain embodiments, the first hardened layer is resistant todiffusion of the therapeutic agent from the second hardened layer.

In certain embodiments, the first hardened layer is substantiallyimpermeable to diffusion of the therapeutic agent from the secondhardened layer.

Another aspect of the present invention is a mold assembly for forming atwo-layer ocular implant, the mold assembly comprising: a mold bodycomprising a contact surface with a curved depression formed therein forforming a first curved surface of a polymer layer of the implant; and animpression body comprising a curved protrusion for forming curvature ata second surface of the polymer layer and for forming curvature in asurface of a silicone adhesive layer of the implant.

In certain embodiments, the curved protrusion is for forming curvaturein only the second surface of the polymer layer of the implant and themold assembly further comprises a second impression body comprising asecond curved protrusion for forming the curvature in the surface of thesilicone adhesive layer of the implant.

In certain embodiments, the impression body is mounted on a supportframe configured to allow vertical movement of the impression body andthe support frame while the mold body remains stationary and the supportframe further comprises a means for locking of the position of theimpression body.

In certain embodiments, the mold assembly further comprises a means forcontrolling the thickness of the polymer layer and the silicone adhesivelayer formed by the mold body and impression body.

In certain embodiments, the mold body is cylindrical and dimensioned forinsertion in a centrifuge tube.

In certain embodiments, the surfaces of the depression and theprotrusion are coated with a non-stick material to facilitate removal ofthe implant from the mold body.

In certain embodiments, the non-stick material is Teflon® or aluminum.

Another aspect of the present invention is a method for determining theeffectiveness of the implant as described herein for treatment orprevention of macular degeneration in a rodent, the method comprising:a) placing the implant as described herein in the sub-Tenon's space ofthe eye of the rodent, wherein the rodent is fed with high-fat chowsupplemented with hydroquinone; and b) monitoring the release of thedrug over time by examining the eye of the rodent with histology,electroretinography or changes in gene expression the retinal pigmentepithelium or photoreceptors, thereby indicating the effectiveness ofthe implant against macular degeneration.

Another aspect of the present invention is a method for evaluating theeffectiveness of the implant as described herein for treatment orprevention of macular degeneration in a human, the method comprising: a)placing the implant as described herein into the sub-Tenon's space ofthe eye of the human; and b) examining the eye of the human using atechnique selected from the group consisting of: 2 color (blue, red)microperimetry, low luminance visual acuity, multi-focalelectroretinography, dynamic perimetry, color vision assessment,photo-stress testing and static perimetry, thereby evaluating theeffectiveness of the implant against macular degeneration.

Another aspect of the present invention is a kit for preparing a moldedtwo-layer composite ocular implant comprising a therapeutic agent fortreatment or prevention of a disorder of the eye, the kit comprising: a)a mold assembly for molding the implant; b) a silicone adhesivecomprising a therapeutic agent for forming a first layer; and c) apolymer for forming a second layer.

In certain embodiments, the mold assembly of the kit is the moldassembly described herein which includes a single impression body. Inother embodiments, the mold assembly of the kit is the mold assemblywhich includes two impression bodies.

In certain embodiments, the kit further comprises instructions formaking a molded two-layer silicon composite ocular implant by sequentiallayering of the polymer and the silicone adhesive comprising thetherapeutic agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. A perspective view of an implant according to one embodiment ofthe invention with curved lines 12 and 14 showing the curvature of theupper surface of the implant.

FIG. 2. A top view of the implant of FIG. 1.

FIG. 3: A cross sectional side view of the implant of FIGS. 1 and 2taken along line 3′-3′ of FIG. 2 (along dotted line 14) showing thelower layer 16 and upper layer 18 of the implant with drug particles 20dispersed in the lower layer 16. Features of the implant are omitted forclarity.

FIG. 4. A schematic side slice view showing selected anatomy of an eye Ewith the placement of a perspective view of the implant of FIGS. 1-3 inthe sub-Tenon's space E0. Other structures of the eye E are shown forcontext.

FIG. 5. A magnified view of the rectangular inset 5′ of FIG. 4 showing aperspective view of the implant embodiment of FIGS. 1-4. Also shown areadditional layers of structures and tissues within the eye and diffusionof a drug 20 to the sclera E3 and the choroid E4.

FIG. 6. A perspective view of an embodiment of a mold assembly formanual molding of an implant with features similar to those of theimplant of FIGS. 1-5. This particular mold assembly 5000 includes twodifferent impression bodies for forming inner curved surfaces of the twolayers of the implant. The assembly includes a mold body 5300, a firstimpression body 5100 and a second impression body 5200. To more clearlyshow the protrusions 5102 and 5202 of the impression bodies 5100 and5200, the upper ends of the impression bodies 5100 and 5200 are tiltedin perspective backward into the plane of the page relative to the moldbody 5300 to expose their contact surfaces.

FIG. 7. A perspective view showing the fitting of the first impressionbody 5100 to mold body 5300 in a portion of the same embodiment of themold assembly system (5000) shown in FIG. 6. Arrangement I (left side)depicts the assembled mold body 5300 and impression body 5100 with theperimeter of mold protrusion 5106 of impression body 5100 substantiallyaligned with the perimeter of the mold depression 5306 as indicated bythe label 5106:5306 with polymer P disposed in the depression 5302.Arrangement II (right side) shows the surface of mold body 5300 afterremoval of impression body 5100 (which, for clarity, is shown in atilted perspective backwards into the plane of the page relative to moldbody 5300 as described for FIG. 7). Formation of polymer layer 518 isindicated.

FIG. 8. A perspective view/process diagram showing the sequentialfitting of mold assembly parts 5300, 5100 and 5200 of the mold assemblysystem embodiment of FIGS. 6 and 7 (5000) and provision of polymer P(stippled fill) and a silicone-drug mixture SDM (diagonal brick fill) inthe process of molding an implant 510 comprising an upper polymer layer518 and a lower layer 516 comprising a silicone-drug mixture. In allrepresentations, impression bodies 5100 and 5200 are tilted inperspective relative to mold body 5300 as described in FIGS. 6 and 7.

FIG. 9. A perspective view/process diagram showing the sequentialfitting of mold assembly parts 5300, 5100 and 5200 of the mold assemblysystem embodiment of FIGS. 6-8 (5000) in sequential formation of thesurfaces 526 and 524 of the implant 510. It is seen that the depthdimensions of the depression 5302 and the protrusions 5102 and 5202determine the thickness of the layers 518 and 516 of the implant 510.

FIG. 10. A side view/process diagram showing the operation of adifferent embodiment of the mold assembly system 7000 where a singleimpression body 7100 is used to form both inner surfaces of the twolayer implant as indicated in steps w, x, y and z. This embodimentincludes a support frame that provides for vertical sliding movement(and locking) of the single impression body 7100 with respect to thefixed mold body 7300.

FIG. 11. A schematic diagram of a system 1000 for automatic productionof an implant 110 according to one aspect of the present inventionwherein the layers 160 and 180 of the implant 110 are formed separatelyby an injection molding apparatus 1200 and joined together by a layerassembly module 1270.

DETAILED DESCRIPTION OF THE INVENTION Overview

The present invention provides a molded composite ocular implantcomprising a therapeutic agent for treatment or prevention of a disorderof the eye. Also provided are methods of making the silicone compositeocular implant and using the implant for treatment of various diseasesor disorders of the eye, including tests of the implant withexperimental animals such as rodents. This implant provides sustainedrelease of the therapeutic agent during the treatment or prevention ofthe disorder of the eye. This implant configuration is particularlywell-suited for placement in the sub-Tenon's space (also known as thebulbar sheath), but is not limited thereto and could be installed on orin other eye regions where convenient and useful.

The implants of this invention can be used to treat a number of eyediseases and indications including, for example, age-related maculardegeneration, glaucoma, diabetic retinopathy, uveitis, retinopathy ofprematurity in newborns, choroidal melanoma, chorodial metastasis, andretinal capillary hemangioma.

General Definitions

The following general definitions are supplied in order to facilitatethe understanding of the present invention.

As used herein, the term “nutraceutical” refers to an isolated nutrientthat may have therapeutic benefit against a disease or disorder. Anon-limiting example of a nutraceutical oil is an omega-3 fish oil.

As used herein the term “radius of curvature” refers to the radius of acircle that best fits the curved surface at a given point.

As used herein, the term “permeation agent” refers to a molecule thatincreases the permeability of a therapeutic agent. An ophthalmicpermeation agent increases the permeability of a therapeutic agent withrespect to tissues of the eye.

As used herein, the term “impression body” refers to a body used toalter a surface of another body by pressure. The impression body mayhave one or more features that produce an impression having a specificshape such as a curvature for example.

As used herein, the term “depression” refers to a region of a surfacewhich is lower with respect to the majority of the surface. Morespecifically, the present specification describes a depression in a moldbody which represents a region with a lower surface than the remainderof the contact surface of the mold body.

As used herein the term “ophthalmic permeation agent” (also known as“transport facilitator”) refers to a compound that increases thepermeability of a therapeutic agent into the tissues of the eye.Methylsulfonylmethane is a non-limiting example of an ophthalmicpermeation agent.

As used herein, the term “microperimetry” refers to a technique which isused to assess the visual function of a specific area of the retina andfovea. It provides a quantifiable way to measure the regression orprogression of retinal visual function in the examined eye. A dot oflight is projected onto the retina at a specific intensity and thepatient is asked to confirm reception of the light. Changes in thestimulus intensity followed by the patient response, provides the meansto assess the retinal visual function. Variations in microperimetryinclude dynamic perimetry, two color (red and blue) perimetry and staticperimetry and are known to those skilled in the art.

As used herein, the term “multi-focal electroretinography” refers to atechnique for determining the activity of retinal cells. Whenbioelectrical changes occur within the retina, the change is propagatedto the surface of the cornea. These small (and often very fast) signalscan be captured by an electrode placed on the surface of the cornea. Thesubject fixates on the center of a display containing an array ofhexagons that increase in size from the center outward. Because thenumber of cone photoreceptors per area varies for different parts of theretina, the size of the hexagons is adjusted, so about the same numberof cones will be stimulated by each hexagon. While the subject views thedisplay, a single continuous electroretinogram recording is obtained.

As used herein, an “intraocular implant” refers to a device or elementthat is structured, sized, or otherwise configured to be placed in aneye. Intraocular implants are generally biocompatible with physiologicalconditions of an eye and do not cause adverse side effects. Intraocularimplants may be placed in an eye without disrupting vision of the eye.

As used herein, a “therapeutic component” refers to a portion of anintraocular implant comprising one or more therapeutic agents orsubstances used to treat a medical condition of the eye.

As used herein, “associated with” means mixed with, dispersed within,coupled to, covering, or surrounding.

As used herein, an “ocular region” or “ocular site” refers generally toany area of the eyeball, including the anterior and posterior segment ofthe eye, and which generally includes, but is not limited to, anyfunctional (e.g., for vision) or structural tissues found in theeyeball, or tissues or cellular layers that partly or completely linethe interior or exterior of the eyeball. Specific examples of areas ofthe eyeball in an ocular region include the anterior chamber, theposterior chamber, the vitreous cavity, the choroid, the suprachoroidalspace, the conjunctiva, the subconjunctival space, the episcleral space,the intracorneal space, the epicorneal space, the sclera, the parsplana, surgically-induced avascular regions, the macula, and the retina.

As used herein, an “ocular condition” is a disease, ailment or conditionwhich affects or involves the eye or one of the parts or regions of theeye. Broadly speaking the eye includes the eyeball and the tissues andfluids which constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

An “anterior ocular condition” is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site. Thus, an anterior ocular condition can include adisease, ailment or condition, such as for example, aphakia;pseudophakia; astigmatism; blepharospasm; cataract; conjunctivaldiseases; conjunctivitis; corneal diseases; corneal ulcer; dry eyesyndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal ductobstruction; myopia; presbyopia; pupil disorders; refractive disordersand strabismus. Glaucoma can also be considered to be an anterior ocularcondition because a clinical goal of glaucoma treatment can be to reducea hypertension of aqueous fluid in the anterior chamber of the eye (i.e.reduce intraocular pressure).

A “posterior ocular condition” is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,optic nerve (i.e. the optic disc), and blood vessels and nerves whichvascularize or innervate a posterior ocular region or site. Thus, aposterior ocular condition can include a disease, ailment or condition,such as for example, acute macular neuroretinopathy; Behcet's disease;choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic opthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

The term “biodegradable polymer” refers to a polymer or polymers whichdegrade in vivo, and wherein degradation of the polymer or polymers overtime occurs concurrent with or subsequent to release of the therapeuticagent. Specifically, hydrogels such as methylcellulose which act torelease drug through polymer swelling are specifically excluded from theterm “biodegradable polymer”. The terms “biodegradable” and“bioerodible” are equivalent and are used interchangeably herein. Abiodegradable polymer may be a homopolymer, a copolymer, or a polymercomprising more than two different polymeric units.

The term “treat”, “treating”, or “treatment” as used herein, refers toreduction or resolution or prevention of an ocular condition, ocularinjury or damage, or to promote healing of injured or damaged oculartissue.

The term “therapeutically effective amount” as used herein, refers tothe level or amount of agent needed to treat an ocular condition, orreduce or prevent ocular injury or damage without causing significantnegative or adverse side effects to the eye or a region of the eye.

A Two-Layer Ocular Implant for Treatment of Macular Degeneration

An example embodiment of the ocular implant of the present inventionwill now be described with reference to FIGS. 1 to 5. Skilled artisanswill appreciate that elements in the figures are illustrated forsimplicity and clarity and have not necessarily been drawn to scale. Forexample, the dimensions of some of the features shown in the figures maybe enlarged relative to other elements to better illustrate and/orfacilitate the discussion herein of the embodiments of the invention.Features in the various figures identified with the same referencenumerals represent like features, unless indicated otherwise.Alternative features of alternative embodiments will also be discussedin context of the features of this example embodiment.

One embodiment of the present invention is a curved two-layer compositeocular implant. The curved shape of the implant 10 is indicated bydotted lines 12 and 14 in FIGS. 1 and 2. This shape may be formed byusing a molding process which will be described in detail hereinbelow.

The ocular implant is formed of two curved layers, a lower layer 16 andan upper layer 18 as can be seen in the cross-sectional view of FIG. 3which is taken along line 3′-3′ of FIG. 2. In this particularembodiment, the lower layer 16 is formed of a silicone adhesive whichcontains a therapeutic agent 20. The two layers are demarcated by line26 (FIG. 3). The lower layer 16 has a lower surface 24 which makescontact with the sclera E3 when the implant is in use.

A number of different therapeutic agents can be delivered to the eye bythe ocular implant of the present invention. Such therapeutic agentsinclude, but are not limited to: antibiotic agents such as fumagillinanalogs, minocycline, fluoroquinolone, cephalosporin antibiotics,herbimycon A, tetracycline, chlortetracycline, bacitracin, neomycin,polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin anderythromycin; antibacterial agents such as sulfonamides, sulfacetamide,sulfamethizole, sulfoxazole, nitrofurazone, and sodium propionate;antiviral agents such as idoxuridine, famvir, trisodiumphosphonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI andAZT, protease and integrase inhibitors; anti-glaucoma agents such asbeta blockers (timolol, betaxolol, atenolol), prostaglandin analogues,hypotensive lipids, and carbonic anhydrase inhibitors; antiallergenicagents such as antazoline, methapyriline, chlorpheniramine, pyrilamineand prophenpyridamine; anti-inflammatory agents such as hydrocortisone,leflunomide, dexamethasone phosphate, fluocinolone acetonide, medrysone,methylprednisolone, prednisolone phosphate, prednisolone acetate,fluoromethalone, betamethasone, triamcinolone acetonide, adrenalcorticalsteroids and their synthetic analogues, and 6-mannose phosphate;antifungal agents such as fluconazole, amphotericin B, liposomalamphotericin B, voriconazole, imidazole-based antifungals, tiazoleantifungals, echinocandin-like lipopeptide antibiotics, lipidformulations of antifungals; polycations and polyanions such as suramineand protamine; decongestants such as phenylephrine, naphazoline, andtetrahydrazoline; anti-angiogenesis compounds including those that canbe potential anti-choroidal neovascularization agents such as2-methoxyestradiol and its analogues (e.g., 2-propynl-estradiol,2-propenyl-estradiol, 2-ethoxy-6-oxime-estradiol, 2-hydroxyestrone,4-methoxyestradiol), VEGF antagonists such as VEGF antibodies and VEGFantisense, angiostatic steroids (e.g., anecortave acetate and itsanalogues, 17-ethynylestradiol, norethynodrel, medroxyprogesterone,mestranol, androgens with angiostatic activity such as ethisterone),thymidine kinase inhibitors; adrenocortical steroids and their syntheticanalogues including fluocinolone acetonide and triamcinolone acetonideand all angiostatic steroids; immunological response modifying agentssuch as cyclosporineA, Prograf (tacrolimus), macrolideimmunosuppressants, mycophenolate mofetil, rapamycin, and muramyldipeptide, and vaccines; anti-cancer agents such as 5-fluorouracil,platinum coordination complexes such as cisplatin and carboplatin,adriamycin, antimetabolites such as methotrexate, anthracyclineantibiotics, antimitotic drugs such as paclitaxel and docetaxel,epipdophylltoxins such as etoposide, nitrosoureas including carmustine,alkylating agents including cyclophosphamide; arsenic trioxide;anastrozole; tamoxifen citrate; triptorelin pamoate; gemtuzumabozogamicin; irinotecan hydrochloride; leuprolide acetate; bexarotene;exemestrane; epirubicin hydrochloride; ondansetron; temozolomide;topoteanhydrochloride; tamoxifen citrate; irinotecan hydrochloride;trastuzumab; valrubicin; gemcitabine HCL; goserelin acetate;capecitabine; aldesleukin; rituximab; oprelvekin; interferon alfa-2a;letrozole; toremifene citrate; mitoxantrone hydrochloride; irinotecanHeL; topotecan HCL; etoposide phosphate; gemcitabine HCL; andamifostine; antisense agents; antimycotic agents; miotic andanticholinesterase agents such as pilocarpine, eserine salicylate,carbachol, diisopropyl fluorophosphate, phospholine iodine, anddemecarium bromide; mydriatic agents such as atropine sulfate,cyclopentane, homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; differentiation modulator agents; sympathomimeticagents such as epinephrine; anesthetic agents such as lidocaine andbenzodiazepam; vasoconstrictive agents; vasodilatory agents;polypeptides and protein agents such as angiostatin, endostatin, matrixmetalloproteinase inhibitors, platelet factor 4, interferon-gamma,insulin, growth hormones, insulin related growth factor, heat shockproteins, humanized antiIL2 receptor mAb (Daclizumab), etanercept, monoand polyclonal antibodies, cytokines, antibody to cytokines;neuroprotective agents such as calcium channel antagonists includingnimodipine and diltiazem, neuroimmunophilin ligands, neurotropins,memantine and other NMDA antagonists, acetylcholinesterase inhibitors,estradiol and analogues, vitamin B12 analogues, alpha-tocopherol, NOSinhibitors, antioxidants (e.g. glutathione, superoxide dismutase),metals like cobalt and copper, neurotrophic receptors (Akt kinase),growth factors, nicotinamide (vitamin B3), alpha-tocopherol (vitamin E),succinic acid, dihydroxylipoic acid, fusidic acid; celltransport/mobility impending agents such as colchicine, vincristine,cytochalasin B; carbonic anhydrase inhibitor agents; integrinantagonists; lipophilic agents such as Idebenone, rapamycin,2-cyano-3,12 dioxooleana-1,9 dien-28-imidazolide (CDDO-Im),2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide(CDDO-ethyl amide), and 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oicacid trifluoroethyl amide (CDDO-TFEA); and lubricating agents. Any ofthese therapeutic agents may be included in the ocular implant eithersingly or in combinations thereof.

This listing of therapeutic agents is illustrative, and not exhaustive.Other drugs that could be delivered by the ocular implant include, forexample, thalidomide. Reference can be made to Remington'sPharmaceutical Sciences, Mack Publishing Press, Easton, Pa., U.S.A., toidentify other possible therapeutic agents for the eye. Anypharmaceutically acceptable form of the agents can be used, such as thefree base form or a pharmaceutically acceptable salt or ester thereof.In this particular embodiment, the dosage of the therapeutic agentprovided by the implant is in the range of 1-100 mg, which is anappropriate dosage for a drug such as sulforaphane which is used in thetreatment of macular degeneration.

The upper layer 18 is formed of a polymer which may be a siliconepolymer or another polymer. Examples of polymers suitable for formingthe upper layer 18 include, but are not limited to, polyvinyl acetate,cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate,ethylene ethylacrylate co-polymer, polyethyl hexylacrylate, polyvinylchloride, polyvinyl acetals, plasiticized ethylene vinylacetatecopolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloridecopolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal,polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticizedpolyvinyl chloride, plasticized nylon, plasticized soft nylon,plasticized polyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene,polyvinylidene chloride, polyacrylonitrile, cross-linkedpolyvinylpyrrolidone, polytrifluorochloroethylene, chlorinatedpolyethylene, poly(1,4′-isopropylidene diphenylene carbonate),vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethylfumarate copolymer, silicone rubbers, medical gradepolydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonatecopolymers, vinylidene chloride-vinyl chloride copolymer, vinylchloride-acrylonitrile copolymer or vinylidene chloride-acrylonitridecopolymer or any suitable equivalent of these polymers or combinationsthereof. In certain alternative embodiments, the polymer is a siliconeadhesive which may be the same as the silicone adhesive used to form thelower layer 16.

As noted above, the lower layer 16 is formed of a medical grade siliconeadhesive, generally is a polydimethylsiloxane (PDMS)-based compound. Thesilicone adhesive is biologically (physiologically) inert and is welltolerated by body tissues. Suitable silicones for use in the practice ofthis embodiment include MED-6810 silicone, MED1-4213, MED2-4213silicone, which can be obtained from NuSil Technology LLC (Carpinteria,Calif., USA). Other biocompatible silicone adhesives may be used and canbe adapted for use in preparation of implants according to certainalternative embodiments of the present invention. The time andtemperature needed to cure the silicone will depend on the silicone usedand the drug release profile desired. These silicones, if left to cureat room temperature (e.g., 20-30° C.) will require about 24 hours ormore to cure. The cure rate will increase with increasing curetemperatures. For instance, MED2-4213 silicone will cure in about 30minutes at about 100° C. As will be discussed in more detail below, themore quickly the silicone is cured, the less opportunity for therapeuticagent to leach out of the layer. In some cases, a catalyst such asplatinum may be used to induce curing.

Dimensions of the ocular implant may vary. However, in this particularembodiment, the implant 10 has a diameter of 7 mm and a thickness of 2mm. In this particular embodiment, each of the two layers 16 and 18 is 1mm thick. In this particular embodiment, the upper surface 22 of theupper layer 18 has a radius of curvature of 5 mm for generallyconforming to the radius of curvature of the surface of Tenon's capsuleE1 of an average human eye (as indicated in FIG. 5). Likewise, the lowerlayer 16 is also curved with a similar radius of curvature configured togenerally conform to the radius of curvature of the sclera E3 of anaverage human eye. These dimensions provide the implant 10 withcharacteristics appropriate for implantation with scleral contact in thesub-Tenon's space E0 of a human. It will be understood by the skilledperson that these dimensions should be modified appropriately for animplant designed for use in an experimental animal such as a rat, mouseor rabbit for example. Armed with the knowledge of average dimensions ofthe eye and radii of curvature of Tenon's capsule and sclera of thechose experimental animal, the dimensions of an ocular implant accordingto may be selected by the skilled person and appropriate molding toolsmay be constructed without undue experimentation.

It is advantageous to provide the ocular implant with an upper layer 18which is generally resistant to diffusion of the therapeutic agent 20which is dispersed in the lower layer 16. In certain embodiments, theupper layer 18 is impermeable to the therapeutic agent 20. In otherembodiments, the therapeutic agent 20 has a rate of diffusion within theupper layer 18 which is significantly less than the rate of diffusion ofthe therapeutic agent 20 out of the lower layer 16 and into the sclera.In this context, the term “significantly less” means 30%, 40%, 50%, 60%,70%, 80%, 90% or 99% less than the rate of diffusion of the therapeuticagent 20 out of the lower layer 16 and into the sclera E3. The reduceddiffusion characteristics of the therapeutic agent 20 in the upper layer18 relative to the lower layer 16 provide the advantage of preventingloss of the therapeutic agent 20 to tissues where it is not needed. Thereduced rate of diffusion of the therapeutic agent 20 through the upperlayer 18 thereby encourages unidirectional diffusion of the therapeuticagent 20 from the lower layer 16 into the sclera E3 and choroid E4 fortransfer to the macula E6 where its desired mechanism of action will beeffected. A further advantage provided by the reduced diffusioncharacteristics of the therapeutic agent 20 in the upper layer 18relative to the lower layer 16 is gained in preventing the therapeuticagent 20 from entering the lymphatic system via Tenon's capsule E1 andthe conjunctiva E2 for transfer to other tissues where it may causeundesirable side-effects. Thus, in certain alternative embodiments ofthe present invention, the upper layer 18 or lower layer 16 furtherincludes an agent that blocks lymphatic absorption.

In this particular embodiment, the thickness of the implant is 2 mm withthe two layers 16 and 18 each being 1 mm in thick. The skilled personwill appreciate that the thickness of each layer may be modifiedaccording to various embodiments of the invention, which may includevariations with respect to the composition of silicone adhesive of thelower layer, the polymer of the upper layer, or the properties of drugsand/or formulations thereof used in the implant. The dimensionalthickness may be modified appropriately by the skilled person withoutundue experimentation.

In this particular embodiment, the drug 20 in the lower layer 16 is anNrf2 regulator such as sulforaphane, which is used in the treatment ofmacular degeneration. The drug is released over time as the drugparticles 20 diffuse through the lower layer 16.

Positioning of the implant 10 with respect to the anatomical structuresof an eye E is indicated in FIGS. 4 and 5. In FIG. 4, the features ofthe implant 10 are omitted for clarity. For convenient reference, theanatomical structures shown in FIGS. 4 and 5 include the sub-Tenon'sspace E0, Tenon's capsule E1 (also known as the bulbar sheath), thesclera E3, the choroid E4 (shown in FIG. 5 only), the optic nerve E5,the macula E6, the vitreous humor E7 and the upper and lower eyelids E8and E9.

Referring now to FIG. 5 (which represents a magnification of the insetlabeled 5′ in FIG. 4) there is provided additional detail regarding theplacement of the implant 10. The implant 10 is located in thesub-Tenon's space E0 with its lower surface 24 resting upon the surfaceof the sclera E3. It is also seen that the upper surface 22 of theimplant 10 has a curvature which generally conforms to the curvature ofthe surface of Tenon's capsule E1. This feature provides the advantageof minimizing discomfort to the eye as a result of contact of Tenon'scapsule E1 with upper edges of the implant 10. The curved upper surface22 is smooth and does not have sharp edges which would otherwise causeirritations and/or damage to the tissues of Tenon's capsule and possiblyalso the conjunctiva E2 in the event that a sharp edge of an alternativeimplant were to completely puncture Tenon's capsule E1 and penetrate theconjunctiva E2.

Drug particles 20 will be released downward to the sclera E3 asindicated by the arrows in FIG. 5, because they are concentrated in thelower layer 16 and because the upper layer 18 is generally resistant todiffusion of the therapeutic agent 20 as described above. In FIG. 5, itis shown that three drug particles 20B have diffused from the lowerlayer 16 through the sclera E3 to the choroid E4 and one drug particle20A has diffused from the lower layer 16 to the sclera E3. These drugparticles 20A and 20B are expected to be transferred by either diffusionor an active physiological mechanism, or a combination thereof, to themacula E6 where the desired pharmaceutical effect will be obtained.Notably, FIG. 5 does not include arrows indicating diffusion of thetherapeutic agent 20 into the upper layer 18 and to upper tissues inTenon's capsule E1 and the conjunctiva E2. This is due to resistance ofthe upper layer 18 to diffusion of the therapeutic agent 20.

In certain embodiments, the implant 10 is provided with a sutureplatform (not shown) which can be formed as part of the implant tofacilitate attachment of the implant 10 to the sclera E3. An implanthaving a suture platform with a mesh contained therein to hold suturesin place is described in U.S. Pat. No. 7,658,364 (which is incorporatedherein by reference in entirety). The implant described herein can bemodified without undue experimentation to include such a suture platformby modification of the molding processes which will be described indetail hereinbelow. Alternatively the implant of the invention may alsobe fixed to a suture stub as described also in U.S. Pat. No. 7,658,364.

A mold assembly comprising two impression bodies and molding processusing this mold assembly for forming a two-layer ocular implant.

In accordance with further aspects of the present invention, there isprovided a mold assembly and molding process for forming a two-layerocular implant. One particular embodiment of the mold assembly is shownin FIG. 6. This mold assembly embodiment is suitable for manualmanipulation and may be adapted for automated use as well. Thisembodiment will be first described in terms of its structure anddescription of its manner of operation and will follow in context ofFIGS. 7-9 wherein the reference numeral scheme is the same as that ofFIG. 6.

The mold assembly of this particular embodiment is a three-piece moldassembly 5000 comprising a mold body 5300 which includes a depression5302 in its upper contact surface 5304. The depression 5300 is providedwith a downward curving inner surface as shown by dotted lines 5312 and5314 (in the same manner as shown for implant 10 of FIG. 1). This curvedinner surface 5302 provides the means for forming a curvature in theupper surface of the upper polymer layer of the implant as exemplifiedby surface 22 in FIGS. 1-3. The perimeter of the depression 5302 isshown at 5306.

Mold assembly 5000 also includes a first impression body 5100 whichincludes a protrusion 5102 on the mold contact surface 5104. Theprotrusion 5102 is downwardly curved as generally indicated by dottedlines 5112 and 5114. The perimeter of protrusion 5102 is shown as 5106and in this particular embodiment, the perimeter 5106 of protrusion 5102has a diameter similar to the diameter of the depression 5302 in moldbody 5300. It is this curved protrusion 5102 that provides the means forforming a curvature in the boundary surface of the upper polymer layerof the implant as exemplified by surface 26 in FIGS. 1-3. The perimeterof the protrusion 5102 is shown at 5306.

The mold assembly 5000 also includes a second impression body 5200. Thissecond impression body 5200 is generally similar to that of the firstimpression body 5100 with the exception that its protrusion 5202 has asmaller diameter as indicated at perimeter 5206 on contact surface 5204.In certain alternative embodiments, the radius of curvature of thisprotrusion 5202 is the same as the radius of curvature of the protrusion5102 of impression body 5100. In the present embodiment, the curvatureof protrusion 5202, as indicated by dotted lines 5212 and 5214 isdifferent from that of protrusion 5102 of the first impression body5100. It is this shallower protrusion 5202 that provides the means forforming a curvature in the lower surface of the lower silicone-druglayer of the implant as exemplified by surface 24 in the implantembodiment shown in FIGS. 1-3.

Notably, parts 5100, 5200 and 5300 are shown as cylinders in thisembodiment. In this particular embodiment, this shape is selected toenable these parts to fit snugly into an appropriately dimensionedcentrifuge tube for degassing of the materials used to form the implant,prior to initiation of the molding and/or the curing process. It isadvantageous to ensure that the silicone adhesive is degassed prior tomolding of the implant. This results in unhindered diffusion of the drugthrough the silicone, as air bubbles or pockets are eliminated whichotherwise would not permit such diffusion. As a result, a controlled andpredictable drug release rate can be obtained. In this embodiment,centrifugation is used to degas the silicone adhesive by adding thesilicone adhesive containing the drug particles to a 50 mL assay tubeand centrifuging this tube for 2 minutes at 1-4 k RPM. Alternativedegassing techniques may include vacuum degassing techniques which canbe adapted for the present invention without undue experimentation.

FIG. 7 indicates the functionality of the mold body 5300 and the firstimpression body 5100 with respect to each other. It should be understoodthat the operation of the mold body 5300 and the second impression body5200 with respect to each other will be generally similar. In FIG. 7,several reference numerals are omitted for clarity but the parts of themold assembly shown in FIG. 7 should be understood as being the same asthose referenced in FIG. 6. Polymer P is added to the depression 5302 ofmold bottom 5300 as indicated by the stippled arrow. Optionally, themold body 5300 containing the polymer in depression 5302 may then beplaced in a centrifuge tube and subjected to centrifugation to degas thepolymer prior to molding and curing (as described above). Then, thefirst impression body 5100 is fitted to mold body 5300 such that surface5104 makes contact with surface 5304 and the perimeter 5106 of theprotrusion 5102 is substantially aligned with the perimeter 5306 of thedepression 5302 of the mold body 5300 (as indicated in Arrangement I onthe left side of FIG. 7). The alignment of perimeters 5306 and 5106 isindicated by the dotted line labeled 5106:5306 in FIG. 7. When the upperpolymer layer 518 of the implant 510 (see FIG. 8) has been formed by themold body 5300 and the first impression body 5100, the first impressionbody 5100 is removed (as shown in Arrangement II shown on the right sideof FIG. 7). It is now seen that excess polymer P covers some of the topsurface of mold body 5300. This excess polymer P may be trimmed away atthis stage to facilitate tight fitting of the second impression body5200 which is indicated in more detail in FIG. 8. An optional device fortrimming excess materials is described hereinbelow. At this stage, theupper polymer layer 518 has been formed and the curing process may beinitiated. The curing process may be initiated with the first impressionbody 5100 in place—to provide some hardness to the polymer layer.Alternatively, curing may be initiated before the impression body 5100is fitted to the mold body 5300. In other alternative embodiments, thecuring process is completed while the impression body 5100 remainsfitted to the mold body 5300.

Shown in FIG. 7 (and omitted in FIGS. 6 and 8 for clarity) is a guideset comprising a pair of rails 5109 fixed to the first impression body5100. This guide set provides the means for conveniently aligning theimpression body 5100 with mold body 5300. It should be understood thatthis feature is optional and, although not shown as such in thesefigures, may also be provided on the second impression body 5200 or onany molding parts provided in alternative embodiments of the moldassembly of the present invention. Such a guide set may comprise morethan two rails and the guide set may be formed integrally with theimpression body part instead of being a separate part attached thereto.

FIG. 8 shows a process which uses the same mold assembly 5000 of FIGS. 6and 7 for constructing a two-layer implant 510. In step a, polymer P isadded to depression 5302 of mold body 5300 and the first impression body5100 is fitted thereto as shown on the left side of FIG. 7.

When the first impression body 5100 is removed from mold body 5300, asshown in step b, it is seen that the polymer has been molded in the formof the upper polymer layer 518 and that excess polymer P covers some ofthe top surface of mold body 5300 (as also shown in FIG. 7). This excesspolymer is trimmed at the perimeter 5306 of the depression 5302 suchthat only the polymer layer 518 remains. In alternative embodiments, itmay be possible to avoid trimming at this stage if the excess polymer Pdoes not interfere with subsequent molding steps which are describedbelow.

This polymer layer 518 in its present orientation within the depression5302 is defined by a lower downward curvature formed by depression 5302and upper downward curvature formed by the molding action of theprotrusion 5102 of the first impression body 5100. The curing processmay be initiated and/or accelerated at this stage (not shown). Thecuring process may be begun with the first impression body 5100 inplace, in order to provide some hardness to the polymer layer.Alternatively, curing may be initiated before the mold is in place. Inother alternative embodiments, the curing process is taken to completionwhile the impression body 5100 remains fitted to the mold body 5300.

In step c, the silicone-drug mixture SDM is added to the polymer layer518 which remains within depression 5302 of mold body 5300. It isadvantageous at this stage to ensure that the polymer layer 518 isessentially completely cured in order to avoid mixing of thesilicone-drug mixture SDM with the polymer P. It is also advantageous toconduct another degassing procedure at this stage. The mold body 5300 isplaced in a centrifuge tube and centrifuged for 2 minutes at 1-4 k RPMto remove gas bubbles and ensure consistent diffusion of the drugthrough the silicone adhesive layer (as described above). Once thedegassing procedure is complete, the second impression body 5200 isfitted to mold body 5300. In another embodiment, the degassing procedureis conducted while the mold assembly of parts 5300 and 5100 is assembledand also when the mold assembly of parts 5300 and 5100 is assembled. Inthis particular embodiment, the protrusion 5202 has dimensions differentfrom the protrusion 5102 of the first impression body 5100 because asignificant portion of the volume of depression 5302 is occupied by thecured (or curing) polymer layer 518 and it is not desirable to compressthe polymer layer 518 as compression may cause damage. The fitting ofthe second impression body 5200 to the mold body 5300 places theperimeter of the protrusion 5202 of the second impression body 5200substantially centrally within the perimeter of the depression 5302 ofthe mold body 5300. The curvature of the interface 526 (see inset ofFIG. 8) between the polymer layer 518 and the silicone-drug layer 516 isformed by the hardened surface of the cured polymer layer 518 (which hasthe effect of acting as a mold surface). The downwardly curving uppersurface of the silicone-drug layer 516 (as oriented in the inset of FIG.8) is formed by the protrusion 5202 of the second impression body 5200.

As shown in step d, when the second impression body 5200 is removed fromthe mold body 5300, it is seen that excess silicone-drug mixture SDMcovers part of the upper contact surface 5304 of the mold body 5300.This excess silicone-drug mixture SDM is then trimmed away. In certainembodiments, this trimming may optionally be performed using anappropriately dimensioned punching device (not shown) which isconfigured to cut a consistent circular shape through cured or partiallycured layers 516 and 518. It may be advantageous to also use thispunching device to remove the excess polymer P in step b as noted above.Advantageously, the punching device is coated with a material thatenables cutting through cured layers 516 and 518 but does not causedamage to the upper contact surface 5304 which is preferably coated withTeflon® (polytetrafluoroethylene), aluminum or other material thatfacilitates removal of the molded implant 510 from the mold body 5300.Teflon is durable with respect to the temperatures required for curingthe silicone, which is generally about 150° C., and after curing, theimplant complex can be peeled off of the mold completely and the moldcan be reused.

The final product of this process is the molded two-layer implant 510which is shown in the inset of FIG. 8.

FIG. 9 shows perspective diagrams of the mold assembly system 5000 (asdiscussed above) to indicate more clearly how the curved interfacesurface 526 and the sclera-contacting surface 524 of the implant 510 areformed by the system 5000. Arrows A526 and A524 indicate the extent oftravel of the protrusions 5102 and 5202, respectively. It is this extentof travel which defines the thickness of each of the layers 518 and 516and which indicate how the surfaces 526 and 524 of the implant 510 aresequentially formed by the protrusions 5102 and 5202. The downwardtravel of the protrusion 5102 is halted when the contact surface 5104 ofthe first impression body 5100 encounters the contact surface 5304 ofthe mold body 5300. Likewise, the downward travel of the protrusion 5202is halted when the contact surface 5204 of the first impression body5200 encounters the contact surface 5304 of the mold body 5300. Thedimensions of the protrusions 5102 and 5202 therefore are selected inconjunction with the depth of the depression 5302 of the mold body 5300and the position of the formed interface surface 526 to provide layers518 and 516 of the implant 510 with predetermined thicknesses. In oneembodiment, the depression 5302 and protrusion 5102 cooperate to mold apolymer layer 518 with a thickness of 1 mm because the space between thesurface of the depression 5302 and the protrusion 5102 is 1 mm when thesurfaces 5304 and 5104 are in contact with each other. The upper surface526 (in the orientation shown in FIG. 9) of the polymer layer 518 thencooperates with the protrusion 5202 of the second impression body 5202to mold a silicone-drug layer 516 with a thickness of 1 mm because thespace between surface 526 and protrusion 5202 is also 1 mm. Therefore,the thickness of the entire implant 510 of this embodiment is 2 mm. Theupper surface 524 (in the orientation shown in FIG. 9) is also curvedand configured to contact the sclera as shown in FIG. 5. The skilledperson will recognize that changing the dimensions of the depression,5302, and/or the protrusion 5102 and/or the protrusion 5202 will lead toproduction of implants with layers 516 and/or 518 of varying thicknessesand with varying radii of curvature. Therefore, any desired goal ofthickness and radius of curvature of layers of the implants according tovarious embodiments of the invention may be obtained without undueexperimentation.

The materials used to form the mold body parts 5300, 5100 and 5200 mayvary. Advantageously, they are formed by injection molding of plasticsor by 3D printing methods (additive manufacturing) and have contactsurfaces 5304, 5104 and 5204 coated with Teflon®, aluminum or othernon-stick material as noted above. The materials and coatings andoptional compatible punching devices may be designed, constructed andtested by the skilled person without undue experimentation.

The properties of the polymer layer 518 and the silicone-drug layer 516may be altered for maximum benefit by selection of an appropriatepolymer for the polymer layer 518 and by altering curing processes. Theextent of curing of layers 516 and 518 is expected to have an effect onthe rate of diffusion of a given drug through that layer. Curing may beconducted over various lengths of time at room temperature or attemperatures as high as 50° C. for either or both of the layers 516 and518. Experiments conducted to optimize the properties of the layers 516and 518 can be performed routinely by the skilled person. Catalysts suchas peroxide or platinum or photo-initiators such as LEDs may also beused to fine-tune the curing process. Other catalysts andphoto-initiators for curing of biocompatible silicone adhesives areknown in the art and can be selected for use with aspects of the presentinvention without undue experimentation.

In an alternative embodiment, the protrusions 5102 and/or 5202 may beprovided by separate parts which can be alternatively connected to asingle impression body part by a common coupling system such as apress-fit mechanism (not shown). Such an alternative mechanism may bedesigned and formed in plastic molded parts without undueexperimentation.

While the embodiment of the mold assembly described in this section hastwo impression bodies 5100 and 5200 it may be possible in alternativeembodiments, to dispense with the second impression body part 5200 incases where the initially formed and cured polymer layer 518 is ofsufficient flexibility that compression by the first impression body5100 can be used to form the sclera-contacting curvature of thesilicone-drug layer 516 without damage to the cured polymer layer 518.Such an alternative embodiment is described hereinbelow.

A mold assembly comprising a single impression body with a support frameand a molding process employing this mold assembly for forming atwo-layer ocular implant

In accordance with an additional aspect of the present invention, thereis provided an additional mold assembly embodiment shown in FIG. 10.This mold assembly 7000 includes only a single impression body 7100 (incontrast to the other mold assembly embodiment described above whichincludes two mold impression bodies, each configured to form curvaturein different surfaces). This particular mold assembly 7000 is providedwith a support frame that enables slidable motion of the impression body7100 with respect to the fixed mold body 7300 and locking of theimpression body 7100 at predetermined positions for formation of twodifferent curved surfaces in the two-layer implant—the interface surfaceas exemplified by surface 26 in FIG. 3 and the sclera-contacting surfaceof the silicone-drug layer of the implant as exemplified by surface 24in FIG. 3.

This mold assembly 7000 includes a support frame which includes a base7151 to which is attached a vertical support member 7153 equipped with avertically slidable sleeve 7157. Sleeve 7157 has a locking mechanism7155 provided by a screw clamp or other such locking arrangement whichserves to halt the motion of the sleeve 7157 with respect to thevertical support member 7153. A horizontal arm 7159 is fixed to sleeve7157 and includes an optional handle 7161 that can be gripped by a userto assist in effecting vertical movement of the arm 7159 by sliding ofthe sleeve 7157 over the vertical support member 7153. The verticalsupport member 7153 is also provided with a vertically slidable andlockable block 7163 which will prevent further vertical downwardmovement of the impression body when it is disposed at any locationabove the upper surface of mold body 7300.

Impression body 7100 is fixed to the lower surface of the arm 7159 andincludes guide rails 7109 to ensure alignment of impression body 7100with mold body 7300 which is fixed to the base 7151. Impression body7100 is provided with a protrusion 7102 which is used to form two of thecurved surfaces of the two-layer implant.

The outline of the mold body depression is shown with a dashed line at7302. It is this depression that forms the upper curved surface of thepolymer layer as exemplified by surface 22 in FIG. 3.

The four steps of this process are indicated as steps w, x, y and z inFIG. 10. In step w (upper left), impression body 7100 is first locked inplace above the mold body 7300 and then polymer P is added to thedepression 7302. Then impression body 7100 is unlocked and lowered byvertical downward movement of arm 7159. Impression body 7100 then stopswhen it encounters the upper surface of the mold body 7300 as shown instep x (upper right). In this manner, the polymer occupying thedepression 7302 is formed with two curved surfaces into a polymer layerwhose location is indicated at 718. This polymer layer is then curedaccording to processes described hereinabove.

Prior to step y (lower left), impression body 7100 is raised and lockedinto place by the locking mechanism 7155. The block 7163 is then movedfrom its original position at 7163A to a higher position indicated at7163B and locked into place via its screw clamp mechanism. Then asilicone-drug mixture SDM is added to the exposed curved surface of thepolymer layer which resides within the depression 7302 of mold body7300. The locking mechanism 7155 is then disengaged and the impressionbody 7100 is lowered until the lower end of the sleeve 7157 encountersthe upper end of the block 7163 (at position 7163B). At this position,the block 7163 prevents further downward movement of the impression body7100. The result of this action is shown at step z (lower right) whereit is seen that the protrusion 7102 of impression body 7100 is halted inits downward movement and forms a curved surface in the silicone-drugmixture residing on top of the polymer layer indicated at 718. Theformation of this curved surface defines the shape of the silicone-druglayer as indicated at 716. The impression body 7100 may then be raisedand locked into place on the vertical support member 7153.

After appropriate curing of the silicone-drug layer 716, the finishedtwo-layer implant (not shown) may then be removed from the mold assembly7000.

The skilled person will recognize that this mold assembly 7000 providesthe means for preparing two-layer ocular implants with variations in thedimensions of the layers 716 and 718 according to the placement of theprotrusion 7102 of the impression body 7100 which is provided by themovement and locking mechanisms of the sleeve 7157 and the block 7163provided on the vertical support member 7155. It is expected to beadvantageous to provide markings in the vertical support to indicatepositions for the block 7163 to provide layers of predeterminedthickness (not shown). The positions of these markings can be determinedby the skilled person without undue experimentation.

The skilled person will also appreciate that this mold assembly can bemodified in alternative embodiments to replace protrusion 7102 with asecond protrusion of different dimensions, if needed. This can be doneif protrusion 7102 is a removable part (with a snap-fit mechanism)rather than being integrally formed with the impression body.Alternatively, the entire impression body 7100 may be removed from thesystem 7000 and replaced with a different impression body (not shown)that has a protrusion with different dimensions than that of protrusion7102.

These assemblies and methods for preparing the implant of this inventionprovide a two-layer implant having a controlled thickness of degassedsilicone with no significant variability in the thickness in the layer,provided the method steps remain consistent. Also, rigorouspost-production quality control inspections (including measuringindividual implant release rates before in vivo use) of the implantproducts are not necessary. This reduces the chances for contaminationof the device from additional handling as well as the cost of making thedevices.

Kit for Production of Two-Layer Ocular Implants

The present invention also contemplates a kit for production oftwo-layer ocular implants. The kit may include any or all of thecomponents and features thereof which are described above with referenceto FIGS. 6-9. In a very basic embodiment, the kit includes a) a moldbody with a depression on its contact surface; and b) an impression bodywith a protrusion on its contact surface configured to form a polymerlayer with curved upper and lower surfaces and to also form asilicone-drug layer with curved upper and lower surfaces. Thisparticular embodiment is used in conjunction with polymer and siliconeadhesive materials provided separately which yield resilient curedlayers that are resistant to damage by pressure of the upper mold bodypart against both layers.

An alternative embodiment of the kit further includes c) a secondimpression body with a protrusion on its contact surface which isconfigured to form the sclera-contacting surface of the silicone-druglayer.

An alternative embodiment of the kit further includes d) polymer andsilicone materials for forming the layers of the two-layer ocularimplant.

In some embodiments of the kit, the mold assembly body parts arecylindrical and the kit further includes e) centrifuge tubes forconducting degassing procedures.

In a further embodiment, the kit further includes a means for trimmingthe excess polymer and silicone from the contact surface of the moldbody. In certain embodiments, this means for trimming is provided by apunching device dimensioned to consistently cut the perimeter of a twolayer implant to specific dimensions.

In some embodiments, the kit includes instructions for using thecomponents of the kit in a molding process for molding a two-layerocular implant.

System and Process for Automated Mass Production of Ocular Implants

The present invention also contemplates a system for automatedproduction of silicone ocular implants. An example embodiment andoperation thereof will be described and possible modifications ofvarious features will also be discussed in context of the features ofthis example embodiment. In this example embodiment, shown in FIG. 11,there is provided a system 1000 which includes an injection moldingapparatus 1200 for automated production of implants 110. In alternativeembodiments, the injection molding apparatus may be substituted for adifferent apparatus such as a 3D printer which is compatible with thecomponents used in the construction of the implant and capable ofadditive manufacturing of two-layer ocular implants.

The injection molding apparatus 1200 is controlled by a computer atworkstation 1300, which is also networked to either a local database1400 or an internet database 1500. Database 1400 or 1500 containsinformation about ocular therapeutic agents such as their compatibilitywith various silicone adhesives and polymers and their rates ofdiffusion through the silicone adhesives and polymers. The database mayalso contain information about additives such as ophthalmic permeationagents, excipients, and agents that block lymphatic absorption. Thedatabase may also contain information regarding the curing processes fordifferent silicone adhesives and polymers, including heating parameters,catalysts and photo-initiators.

In FIG. 11, the dot-dashed lines represent data communication conduits(which may be provided by wires or by wireless communication) betweenthe workstation 1300 and individual modules and the solid linesrepresent conduits for handling of materials used in construction of theimplants 110. Movement of materials may be effected by robotic means ormanually or by a combination thereof. The skilled person will understandthat alternative embodiments are possible wherein one or more of theautomatic tasks involving data and/or liquid handling communication maybe overridden and performed manually by a user of the system.

The materials used to make the implants may be stored in individuallibraries contained in the laboratory or production plant. In thisparticular embodiment, the libraries include a therapeutic agent library1840, a silicone adhesive library 1820 and a polymer library 1600. Auser can access the database 1400 or 1500 to determine compatibility ofa given therapeutic agent in the library 1840 with respect to siliconeadhesives contained in library 1820 and polymers contained in library1600. Alternatively, the user may select a therapeutic agent from thetherapeutic agent library 1840 and this action will automaticallyinitiate an algorithm stored on the workstation 1300 or accessible viathe internet, which will automatically identify appropriate siliconeadhesives and polymers that will be compatible with the production ofthe two-layer implants 110 and enable a selection to be made. Thealgorithm may further access the inventory of each of the libraries1600, 1820 and 1840 to determine if the desired set of components isavailable in the laboratory or production plant and then provide thisinformation to the user who may then elect to proceed with the currentlyselected production run or elect to choose alternative materials. Thistype of algorithm may be developed without undue experimentation by theskilled person.

Once a production run is initiated by a user, the algorithm providesinstructions to select a silicone adhesive from silicone adhesivelibrary 1820 and send it to a mixing apparatus 1860. In a similarmanner, the algorithm provides instructions to select a therapeuticagent from the therapeutic agent library 1840 and send it to the mixingapparatus 1860 and also provides instructions to select a polymer fromthe polymer library 1600. The transfer of these and other components tovarious locations within the system 1000 may be effected by commerciallyavailable robotic liquid handlers, or may be effected by manualtransfer. Solid particles containing the therapeutic agent may also bedispensed by robotic handlers configured to dispense powders orparticles. Programming of such robotic handlers for tasks performed bythe present embodiment of the system is a routine task for the personwith ordinary skill.

Mixing of the therapeutic agent and the silicone adhesive is performedin a mixing apparatus 1860. One example of such a mixer is theSpeedMixer™ dual asymmetric centrifugal laboratory mixer (FlaxTek Inc.,Landrum, S.C., USA). The mixture is then transferred to a degassingmodule 1880 which in certain embodiments is provided by a centrifuge asdescribed above. The degassing process is performed to remove airbubbles from the silicone adhesive to ensure consistent diffusion ratesof the therapeutic agent through the silicone adhesive. When the mixedand degassed silicone adhesive-drug mixture and the polymer are readyfor further downstream processing, they are then transferred to theirrespective holding containers 1900 and 1700.

In this particular embodiment, the polymer layer 118 of the implant 110is the first layer selected for molding. Instructions are transmittedfrom the workstation 1300 to the robotic system to effect transfer ofthe polymer P from the polymer holding container 1700 to the injectionmolding apparatus 1200 at port A where the polymer P is injected intothe mold formed by mold plates 1251 and 1252 associated with theinjection molding system 1200. If curing is to be accelerated, anoptional curing module 1210 may be included in the system 1000. Thecuring module 1210 may be simply a light source for photo-initiation ofcuring at the mold portion 1251 and 1252 of the injection moldingapparatus 1200 or may be provided by a container containing a liquidcuring catalyst and a liquid handler configured to transfer the liquidcuring catalyst to the injection molding apparatus 1200 at port B fortransfer to the mold plates 1251 and 1252. The curing module 1210 mayalso cure one or both of the layers 116 and 118 while they reside withina layer assembly module 1270 which will be described in more detailhereinbelow. The curing module 1210 may also be under computer controlat the workstation 1300.

In this particular embodiment, when the molding and curing of thepolymer layer of a series of implants 110 is complete, the cured polymerlayer 118 is removed from the mold plates 1251 and 1252. The system 1000is then prepared for the molding of the silicone adhesive layer 116 fromthe silicone-drug mixture SDM. In one embodiment, the mold plates 1251and 1252 are removed and replaced with new mold plates, shown generallyas parts 1261 and 1262 which are configured to form the siliconeadhesive layer 116. This process of replacing the mold plates 1251 and1252 with mold places 1261 and 1262 (as indicated by the double arrow inFIG. 10) may be performed manually or by a robot (not shown). After themold plates 1261 and 1262 are in place, the process of forming thesilicone adhesive layer 116 may then begin. The silicone—drug mixtureSDM (which may also contain other additives such as ophthalmicpermeation agents or agents that block lymphatic absorption of the drug)in holding container 1900 is transferred to the injection moldingapparatus 1200 at port A. This material is injected into the mold plates1261 and 1262 and the silicone adhesive layer 116 is formed and cured,if necessary, by the curing module 1210.

In an alternative embodiment, another injection molding apparatus (notshown) may be provided for molding of the silicone adhesive layer 116instead of substituting mold plates 1251 and 1252 for mold plates 1261and 1262. While this embodiment would be more expensive, it would allowfor more constant production by avoiding the need to clean the injectionsystem and change the mold plates.

At this point, the system has produced a silicone adhesive layer 116containing the therapeutic agent and a polymer layer 118 in separateproduction runs. These two layers are now joined together usingbiocompatible pressure sensitive silicone adhesive glue such as DowCorning BIO-PSA 7-4302 silicone adhesive to form a finished implant 110.Advantageously, this task is automated and performed in layer assemblymodule 1270. In certain embodiments, this layer assembly module 1270 mayinclude a matched pair of custom-designed multi-well plates (not shown)in which one of the plates of the pair is designed specifically to holdthe silicone adhesive layer 116 and the other plate of the pair isdesigned specifically to hold the polymer layer 118. This would allowthe layers to be assembled simply by stacking the plates together suchthat the layers are joined in the proper orientation wherein thesilicone adhesive layer 116 is joined at its upper surface to the lowersurface of the polymer layer 118. The layer assembly module 1270 mayinclude a means for dispensing an adhesive onto either one or both ofthe layers 116 or 118 to fix the two layers together. In alternativeembodiments, there may be sufficient cohesion between layers 116 and 118that an adhesive is not required. The skilled person will recognize thatthe layer assembly module 1270, like a number of other components ofsystem 1000 (e.g. libraries, mixing containers, holding containers etc.)should be considered an optional component of the system and that it ispossible for the layers 116 and 118 to be joined manually with orwithout adhesive.

Administration of or Using the Two-Layer Ocular Implant

To administer the implant, the subconjunctival matrix implant preferablyis placed behind the surface epithelium within the sub-Tenon's space.This is done by a surgical procedure that can be performed in anout-patient setting. A lid speculum is placed and a conjunctival radialincision is made through the conjunctiva over the area where the implantis to be placed. Wescott scissors are used to dissect posterior toTenon's fascia and the implant is inserted. The conjunctiva isreapproximated using a running 10-0 vicryl suture. The eye has manybarriers that do not permit easy penetration of drugs. These include thesurface epithelium on the front (cornea) of the eye and theblood/retinal barrier either within the retinal blood vessels or betweenthe retinal pigment epithelium that both have tight junctions. Theseimplants are generally about 1-2 mm in diameter for small rodent (i.e.,mouse and rat) eyes, 3-4 mm in diameter for rabbit and human eyes and6-8 mm in diameter for equine eyes.

In certain embodiments, an applicator device is used to inject theimplant into the sub-Tenon's space. Such devices are known in the artand have been used for intraocular injections into the vitreous humor ofthe eye, particularly in intraocular lens implantation after cataractsurgery. In certain embodiments, the device is provided with a retractorthat engages the conjunctiva and the surface of Tenon's capsule toproduce an opening into the sub-Tenon's space. The device is alsoprovided with a means for pushing the implant into the sub-Tenon's spacesuch that withdrawal of the device allows the surrounding tissues tocollapse back into place while holding the implant at the desiredlocation.

Additionally, when the implant is placed near the limbus (i.e., the areawhere the conjunctiva attaches anteriorly on the eye) to encourage thedrug diffusion to enter the cornea, it may be preferable to fixate thematrix implant with one or two absorbable sutures (e.g., 10-0 absorbablevicryl sutures). This is done by making holes with a 30 gauge needle inthe peripheral portion of the implant, approximately 250-500 μm awayfrom the peripheral edge of the implant. The holes are made 180 degreesfrom each other. This is done because subconjunctival matrix implants ofthis invention, when placed near the cornea, are at higher risk toextrude because of the action of the upper eye lid when blinking. Whensubconjunctival matrix implants of this invention are placed about 4 mmor more away from the limbus, the sutures are optional.

This matrix implant can deliver therapeutic levels of differentpharmaceuticals agents to the eye to treat a variety of diseases. Usinga rabbit model, drug released from the implant placed in the eyeproduces negligible levels of the drug in the blood. This significantlyreduces the chances of systemic drug side-effects. This implant designof this invention is prepared by unique methodologies and selections ofmaterials leading to and imparting the unique pharmacologicalperformance properties present in the finished devices.

Lipophilic Agents

In accordance with the present invention, the therapeutic agent orcomponent of the implant may comprise, consists essentially of, orconsists of, a lipophilic agent. Such lipophilic agents may be smallmolecules. Lipophilic agents may be released from the implant bydiffusion, erosion, dissolution or osmosis. The drug release sustainingcomponent may comprise one or more biodegradable polymers or one or morenon-biodegradable polymers.

In one embodiment, the intraocular implants comprise a lipophilic agent.Lipophilic agents or other agent which may be employed in the implantsof the present invention include those taught in US Patent Publication,US20140031408, the contents of which are incorporated herein byreference in its entirety.

In another embodiment, intraocular implants comprise a therapeutic agentor component that comprises a lipophilic agent.

Advantageously, the present implants provide a sustained or controlleddelivery of therapeutic agents at a maintained level despite the rapidelimination of the lipophilic agents from the eye. For example, thepresent implants are capable of delivering therapeutic amounts of alipophilic agent for a period of at least about 30 days to about a yeardespite the short intraocular half-lives associated with lipophilicagents. The controlled delivery of lipophilic agents from the presentimplants permits the lipophilic agents to be administered into an eyewith reduced toxicity or deterioration of the blood-aqueous andblood-retinal barriers, which may be associated with intraocularinjection of liquid formulations containing lipophilic agents.

The implants may be placed in an ocular region to treat a variety ofocular conditions, such as treating, preventing, or reducing at leastone symptom associated with non-exudative age related maculardegeneration, exudative age related macular degeneration, choroidalneovascularization, acute macular neuroretinopathy, cystoid macularedema, diabetic macular edema, Behcet's disease, diabetic retinopathy,retinal arterial occlusive disease, central retinal vein occlusion,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser treatment, conditions caused by photodynamic therapy,photocoagulation, radiation retinopathy, epiretinal membranes,proliferative diabetic retinopathy, branch retinal vein occlusion,anterior ischemic optic neuropathy, non-retinopathy diabetic retinaldysfunction, retinitis pigmentosa, ocular tumors, ocular neoplasms, andthe like.

Kits in accordance with the present invention may comprise one or moreof the present implants, and instructions for using the implants. Forexample, the instructions may explain how to administer the implants toa patient, and types of conditions that may be treated with theimplants.

EXAMPLES

The foregoing description will be more fully understood with referenceto the following examples. These examples, are, however, exemplary ofmethods of making and using certain aspects of the present invention andare not intended to impose limits on the scope of the invention asdefined by the appended claims.

Example 1: Administration of a Two-Layer Ocular Implant Containing anNrf2 Regulator Drug in a Mouse Model of Dry AMD

Hydroquinone is known as an oxidant component of cigarette smoke. It hasbeen found that mice treated with hydroquinone may be used as a model ofdry AMD (Espinosa-Heidmann et al., Invest. Ophthal. Vis. Sci., 2006,47-729). Aged male mice (>60 weeks, n=4) are fed a high fat diet (TD88051; Harlan Teklad) supplemented with 0.8% hydroquinone for a minimumof 8 weeks. Alternatively, hydroquinone can be injectedsubconjunctivally for up 4 weeks as an alternate model. Other models ofmacular degeneration including the Y402H CFH transgenic under thecontrol of the ApoE promoter, the Ccl2−/− Cx3cr1−/− mice, the Sod1−/−mice, the OXY rats as well other animal models may also be used.

Implants prepared as described herein are administered to the treatedmice. The implants are circular, 2.0 mm in diameter and 1 mm thick andcontain the Nrf2 regulator sulforaphane at doses of 10 mg and 30 mg. Thesulforaphane content of the implants is determined by dissolvingimplants in 1 mL of phosphate-buffered saline (PBS; pH 7.4) withintermittent stirring followed by HPLC measurements.

It has been discovered that placement of test implants in thesub-Tenon's space of rodents leads to episcleral clearance of the testsubstance (Chan, Pridgen and Csaky, 2010, Exp. Eye Res. 90, 501).Therefore, surgical placement of the implants is performed by incisingthe conjunctiva and Tenon's fascia prior to placement of the implants inthe sub-Tenon's space as far posteriorly as possible.

The mice are then monitored to determine the release of the drug overtime by examining the eye using histology, electroretinography orchanges in gene expression in the retinal pigment epithelium orphotoreceptors. Confirmation of morphological changes in cellsindicating the presence of the drug indicates the effectiveness of theimplant in transfer of sulforaphane to from the implant to thesurrounding tissues in the process of treating macular degeneration.

Example 2: Release Kinetics of a Lipophilic Drug from a Silicone OcularImplant

Without wishing to be bound by theory, it is believed that certaindrugs, particularly highly lipophilic drugs, recrystallize or otherwisemorph into a different crystal form within the matrix of the siliconeimplant and that this change produces improved ocular penetrationrelative to direct injections of the “naked” drug. Alternatively thecontrolled release of smaller particles of highly lipophilic drugs fromthe silicone adhesive implant also results in improved ocularpenetration.

To this end, lipophilic drugs useful in the treatment of oculardisorders may be prepared in the implants of the invention. In thisstudy an experimental ocular implant 2 mm in diameter is prepared whichcontains between 5-80% by weight of a lipophilic drug. In one instancethe drug is solubilized in silicone oil into which it is highly solublein which crosslinker catalyst is added, the solution is mixed, pouredinto a Teflon mold of predetermined size and the implants are placed at100 degrees C. for 30 minute. In a first experiment, the rate of releaseof the drug from the implant into a solution of phosphate-bufferedsaline (PBS) is measured over a period of time, e.g., about 24 hours.

In a related experiment, release of the drug from the same implant ismonitored over a period of multiple days to months with measurements ofthe total amount of drug released (μg) from the implant being obtainedonce each day. Lipophilic drugs may show superior release kinetics.

Example 3: Elution of a Lipophilic Compound from an Episcleral SiliconeImplant into Rodent Ocular Tissues and Comparison with Direct EpiscleralInjections

In a series of experiments, elution of a lipophilic compound from thesame 2 mm ocular implant described in Example 2 is investigatedfollowing episcleral implantation in rodents and compared with directepiscleral injections of similar doses of the same compound. In animalstreated with the ocular implant, a 4 mm punch of tissue comprisingsclera, conjunctiva and choroid (SCC) is obtained daily for five days.The amount of drug in the retinal tissue is determined separately.Concentrations of the lipophilic compound (ng/mL) are then determined.

These results provide an indication that the implant of the inventionfunctions as intended. The determination that higher concentrations of alipophilic ocular drug in ocular tissues can be obtained from theimplant relative to direct episcleral injections provides a basis forthe prediction that other lipophilic drugs can be used in the implantand will function in a similar manner. It is further predicted on thisbasis that the implant of the present invention is useful for treatmentof the ocular disorders described hereinabove.

EQUIVALENTS AND SCOPE

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments in accordance with the invention described herein. The scopeof the present invention is not intended to be limited to the aboveDescription, but rather is as set forth in the appended claims.

In the claims, articles such as “a,” “an,” and “the” may mean one ormore than one unless indicated to the contrary or otherwise evident fromthe context. Claims or descriptions that include “or” between one ormore members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

It is also noted that the term “comprising” is intended to be open andpermits but does not require the inclusion of additional elements orsteps. When the term “comprising” is used herein, the term “consistingof” is thus also encompassed and disclosed.

Where ranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or subrangewithin the stated ranges in different embodiments of the invention, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise.

In addition, it is to be understood that any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Since such embodiments aredeemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the compositions of the invention (e.g., anynucleic acid or protein encoded thereby; any method of production; anymethod of use; etc.) can be excluded from any one or more claims, forany reason, whether or not related to the existence of prior art.

All cited sources, for example, references, publications, databases,database entries, and art cited herein, are incorporated into thisapplication by reference, even if not expressly stated in the citation.In case of conflicting statements of a cited source and the instantapplication, the statement in the instant application shall control.

Section and table headings are not intended to be limiting.

Various references are cited throughout this specification. Each ofthese references is incorporated herein by reference in entirety.

What is claimed is:
 1. A method for forming a molded two-layer ocularimplant, the implant comprising a therapeutic agent for treatment of anocular condition in a human or veterinary animal, the method comprising:(a) dispensing a polymer into a curved depression on a mold body to forma polymer layer, said polymer layer having (i) a curved external surfacewhich is in contact with the bottom of the curved depression of the moldbody wherein the curved external surface of the polymer layer generallyconforms to the radius of curvature of the sub-Tenon's capsule of theeye, and (ii) an exposed upper surface, wherein any excess polymer atthe perimeter of the curved depression on the top surface of the moldbody is trimmed; (b) generating a curvature in the exposed upper surfaceof the polymer layer formed in (a) with a first impression body, saidfirst impression body having a protrusion for generating said curvature,thereby forming a curved polymer layer interface surface; (c) curing thepolymer layer to completion prior to step (d), thereby providing ahardened curved polymer layer interface surface; (d) dispensing adegassed silicone adhesive comprising the therapeutic agent dispersedtherein onto the hardened curved polymer layer interface surface therebyproviding a silicone drug layer with an exposed surface, and optionallydegassing the silicone drug layer while in the mold body; (e) generatinga curvature in the exposed surface of the silicone drug layer comprising(i′) contacting said silicone drug layer with a second impression body,said second impression body having a protrusion for generating saidcurvature and where the fitting of the second impression body places theperimeter of the second impression body substantially centrally withinthe perimeter of the depression by the first impression body, and (ii′)optionally trimming any excess silicone drug polymer on the mold body,thereby forming a curved eye-contacting surface in the silicone druglayer, wherein the curved eye-contacting surface of the silicone druglayer generally conforms to the radius of curvature of the sclera of theeye; and (f) curing the silicone drug layer formed in steps (d)-(e)thereby forming the molded two-layer ocular implant, wherein the polymerlayer of the molded two-layer ocular implant extends circumferentiallybeyond the silicone drug layer of the molded two-layer ocular implantsuch that the surface of the circumferential extension of the polymerlayer is capable of making contact with the sclera of the eye.
 2. Themethod of claim 1 wherein the implant is circular or oval-shaped.
 3. Themethod of claim 1 wherein the polymer layer is resistant to diffusion ofthe therapeutic agent from the silicone layer.
 4. The method of claim 1wherein the polymer layer is substantially impermeable to diffusion ofthe therapeutic agent from the silicone layer.
 5. The method of claim 1wherein the polymer layer and the silicone drug layer are each about 1mm thick.
 6. The method of claim 1 wherein the radius of curvature ofthe curved eye-contacting surface of the silicone layer ranges frombetween about 5 mm to about 6 mm.
 7. The method of claim 1 wherein theresulting molded implant is circular with a diameter ranging betweenabout 1 mm and 8 mm.
 8. The method of claim 1, comprising the step ofmixing an agent that blocks lymphatic absorption with the polymer,wherein said mixing occurs prior to step (a).
 9. The method of claim 8wherein the polymer layer includes an agent that blocks lymphaticabsorption of the therapeutic agent.